HivPhase 1/2ORBITNCT06240520
Optimizing Reversal of HIV Latency With Combination Therapy
A Phase 1/2 study testing Panobinostat 20 MG Oral Capsule, Pyrimethamine 200mg Oral Tablet and Lenalidomide 25 MG Oral Capsule in people with Hiv, run by Erasmus Medical Center at 3 sites in Netherlands.
Trial summary
The ORBIT trial is part of a worldwide search for a functional cure of HIV. One such cure strategy aims to reverse HIV in the reservoir from latency by increasing cell-associated HIV-RNA, which will lead to increased antigen presentation, trigger immune recognition, and facilitate the elimination of reservoir cells… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Hiv
- What is being tested?
- Panobinostat 20 MG Oral Capsule, Pyrimethamine 200mg Oral Tablet and Lenalidomide 25 MG Oral Capsule
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 49 participants
- Where
- 3 sitesNetherlands
- Study dates
- Apr 2024to Oct 2025
- Phase
- Phase 1/2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Documented HIV-1 infection by 4th generation ELISA, Western Blot or PCR.
- ≥ 18 years old.
- World Health Organization (WHO) performance status 0 or 1.
- Current plasma HIV RNA <50 copies/ml measured on the last 2 occasions, with measurements being at least 3 months apart.
- Uninterrupted prescribed ART for a minimum of two consecutive years.
- Considered >95% adherent to ART by treating physician.
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- Current blood CD4+T-cell count of ≥200 cells/mm3
- No clinical signs of cellular immunodeficiency or AIDS.
- Pre-ART plasma HIV RNA ≥1000 copies/mL.
- Confirmed HIV subtype B. People with a high likelihood of subtype B can participate if they live in a HIV subtype B endemic region with HIV acquired there and in whom no HIV sequencing is available or can be done on stored samples.
- People should be considered capable mentally and somatically by their treating physician to understand the informed consent procedure and undergo the study treatment.
Who cannot join
- A potential subject who meets any of the following criteria will be excluded from participation in this study:
- Previous exposure to any of the studied LRAs in the last year
- Acute or chronic co-infection with hepatitis B and/or C by the presence of hepatitis B surface antigen (HBsAg) or hepatitis C virus RNA in blood.
- Co-medication with clinically significant interactions with LRA (see chapter 15.h for list)
- Comorbidities affected by LRA compounds, such as but not limited to: known Glucose-6-phospate-dehydrogenase (G6PD) deficiency with anaemia, untreated haemolysis of any cause or hereditary thrombophilia not currently treated by anticoagulation.
- Prolonged Qtc time >480ms at screening, as measured by electrocardiogram (ECG).
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- Patients of childbearing potential unless double contraceptive measures are taken. Non-childbearing is defined by one of the following criteria: amenorrhoea for ≥ 1 year, premature ovarian failure, assigned male at birth, or having undergone previous bilateral salpingo-oophorectomy, or hysterectomy
- Sexual active patients unwilling to abstain from sex unless willing to use condom protection during and until 1 week after administration of study medication.
- Active malignancy during the past year with the exception of basal carcinoma of the skin, stage 0 cervical carcinoma, Kaposi's sarcoma treated with ARTalone or other indolent malignancies.
- Registered allergies for any of the investigational medical products
- Any lab abnormalities at screening as listed below:
- Moderate kidney impairment, defined as eGFR <50 mL/min
- Moderate hepatic impairment, defined as bilirubin > 3 x upper limit of normal (ULN) or ALT > 3x ULN
- Inadequate blood counts, defined as: Haemoglobin <6.5 mmol/L (males) or <6.0 mmol/L (females), absolute neutrophil count <1000 cells/mm3, thrombocytes <100 x109/L, international standardized ratio >1.6, activated partial thromboplastin time >40 seconds, serum sodium <130 mmol/L, serum potassium <3.0 mmol/L, serum phosphate <0.5 mmol/L, serum calcium <1.9 mmol/L, serum magnesium <0.5 mmol/L.
Trial locations and contacts
3 sites in 1 country.
Netherlands3 sites
Amsterdam University Medical Center
Amsterdam
Michelle Klouwens, MD PhD
Godelieve De Bree, MD PhD
Erasmus Medical Centre
Rotterdam, South Holland, 3015 GD
Rokx Casper, MD PhD
Casper Rokx, MD PhD
University Medical Center Utrecht
Utrecht
Annelies Verbon, MD PhD
Annelies Verbon, MD PhD
About this study
Official title: Optimizing Reversal of HIV Latency With Combination Therapy (Pyrimethamine, Lenalidomide, Panobinostat)
The ORBIT trial is part of a worldwide search for a functional cure of HIV. One such cure strategy aims to reverse HIV in the reservoir from latency by increasing cell-associated HIV-RNA, which will lead to increased antigen presentation, trigger immune recognition, and facilitate the elimination of reservoir cells (so-called 'shock and kill' approach to HIV cure). Participants of the trial are adults with HIV with undetectable viral load that are able to give informed consent to participate in the trial, in total 49 patients will be recruited. The investigational medical compounds in this trial are panobinostat, lenalidomide and pyrimethamine. These are all licensed drugs for other conditions. Participants of this trial will receive a single dose of the IMPs, either as monotherapy or as combination therapy. Sampling will be performed before, during and after medical treatment to evaluate latency reversal, reservoir reduction and safety endpoints. Patients will be recruited from the Erasmus MC, Amsterdam university Medical Center and the University Medical Center Utrecht.
Read the detailed description
Rationale
Despite advances in antiretroviral therapy (ART) that nowadays can fully suppress HIV replication, HIV treatment still has to be taken lifelong due to the persistence of a latent HIV reservoir. This reservoir consists of long-lived memory T-cells in which HIV persists as provirus in the host genome. There is minimal proviral transcriptional activity, and the elimination of these reservoir cells is prohibited by limited antigen recognition and elimination by the immune system. When antiretroviral treatment is stopped, the virus almost universally rebounds from its reservoir, and if left untreated will result in HIV disease progression. Intensive research efforts over the last decade is focused on finding a definitive cure for HIV that would allow people to safely stop their ART without risking viral rebound. One such cure strategy aims to reverse HIV in the reservoir from latency by increasing cell-associated HIV-RNA, which will lead to increased antigen presentation, trigger immune recognition, and facilitate the elimination of reservoir cells (so-called 'shock and kill' approach to HIV cure). Several latency reversal agents have been identified to reactivate HIV transcription in the reservoir. Though current single latency reversal agents are effective in achieving this to a limited extent, they have not resulted in significant HIV reservoir reduction. One explanation could be that a stronger reactivation is needed. As such, we aim to study novel combinations of promising latency-reversing agents with different drug targets to improve HIV latency reversal within the viral reservoir.
Study design:
Open label randomized controlled trial.
Study population:
49 adult people with HIV-1
Intervention:
The investigational drugs are panobinostat, lenalidomide, and pyrimethamine. Patients will be randomized 1:1:1:1:1:1:1 to one of 7 arms to receive a combination of two investigational drugs, one investigational drug or no interventional treatment.
Arm 1: control Arm 2: panobinostat 20mg once orally Arm 3: lenalidomide 25mg once orally Arm 4: pyrimethamine 200mg once orally Arm 5: panobinostat 20mg once orally and lenalidomide 25mg once orally. Arm 6: panobinostat 20mg once orally and pyrimethamine 200mg once orally. Arm 7: lenalidomide 25mg once orally and pyrimethamine 200mg once orally.
Procedures
All participants will have a screening visit including a leukapheresis or venous blood sampling before the intervention between T= -1 to -60 days. Subsequent blood sampling by phlebotomy is at T=0-hour (day 0) before drug administration, and T=2 hours, T=6 hours, T=24 hours (day 1), and T= 2 months (60 days) post study drug administration. An optional second leukapheresis instead of blood sampling by phlebotomy at the last sampling time point is possible. Clinical assessments are at days 0, 1, and 7. Clinical assessment at day 7 can optionally be remote.
- Conditions
- Hiv
- Being tested
- Panobinostat 20 MG Oral Capsule, Pyrimethamine 200mg Oral Tablet, Lenalidomide 25 MG Oral Capsule
- Keywords
- HIV Cure, Shock and kill, Latency reversal, Combination therapy
- Medical subject headings
- Acquired Immunodeficiency Syndrome, Shock
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Panobinostat 20 MG Oral CapsuleDrug
Panobinostat 20mg will be administered once orally
Pyrimethamine 200mg Oral TabletDrug
Pyrimethamine 200mg will be administered once orally
Lenalidomide 25 MG Oral CapsuleDrug
Lenalidomide 25mg will be administered once orally
| Study group | Role | What they receive |
|---|---|---|
| control | No intervention | Not described |
| panobinostat | Experimental | Not described Receives: Drug: Panobinostat 20 MG Oral Capsule |
| lenalidomide | Experimental | Not described Receives: Drug: Lenalidomide 25 MG Oral Capsule |
| pyrimethamine | Experimental | Not described Receives: Drug: Pyrimethamine 200mg Oral Tablet |
| panobinostat + lenalidomide | Experimental | Not described Receives: Drug: Panobinostat 20 MG Oral Capsule; Drug: Lenalidomide 25 MG Oral Capsule |
| panobinostat + pyrimethamine | Experimental | Not described Receives: Drug: Panobinostat 20 MG Oral Capsule; Drug: Pyrimethamine 200mg Oral Tablet |
| lenalidomide + pyrimethamine | Experimental | Not described Receives: Drug: Pyrimethamine 200mg Oral Tablet; Drug: Lenalidomide 25 MG Oral Capsule |
What is being measured
The primary outcome is the main question the study is designed to answer.
Cell-associated HIV RNA
Fold change in cell-associated HIV RNA
Measured: 1 day
Adverse events
The number and severity of clinical and biochemical adverse events considered by the investigator to be related to any of the investigational drugs
Measured: 14 days
Secondary outcomes (1)
HIV reservoir
The change in the HIV reservoir size and genetic composition from baseline to the end of the study
Measured: 120 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted5 Feb 2024
- Study startApr 2024 (estimated)
- Primary completionMay 2025 (estimated)
- Study completionOct 2025 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for HivStudies of the same condition, open and under way.
- More trials run by Erasmus Medical CenterThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Open label randomized controlled trial.
- Masking
- None (open label)
- Enrolment
- 49 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Erasmus Medical Center
- Sponsor type
- University, hospital or other
- Collaborators
- ZonMw: The Netherlands Organisation for Health Research and Development, AIDSfonds
- Responsible party
- Principal investigator, Casper Rokx, Erasmus Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06240520
- Sponsor's protocol ID
- 2024-511192-15-00
- Acronym
- ORBIT
- Status last verified
- Jan 2024
- First submitted
- 26 Jan 2024
- Last updated
- 5 Feb 2024
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: Data will be stored under FAIR use principle for use in future research. Should external researchers want to use this dataset, they can contact the principal investigator. In the case of adequate privacy standards data can be shared under a specific new Data Sharing Agreement
Study at a glance
From the registry record, last updated by the sponsor on 5 Feb 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Optimizing Reversal of HIV Latency With Combination Therapy (Pyrimethamine, Lenalidomide, Panobinostat)
- ClinicalTrials.gov ID
- NCT06240520
- Acronym / sponsor ID
- ORBIT / 2024-511192-15-00
- Conditions
- Hiv
- Keywords
- HIV Cure, Shock and kill, Latency reversal, Combination therapy
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 49 participants (estimated)
- Lead sponsor
- Erasmus Medical CenterUniversity, hospital or other
- Collaborators
- ZonMw: The Netherlands Organisation for Health Research and Development, AIDSfonds
- Study start
- Apr 2024 (estimated)
- Primary completion
- May 2025 (estimated)
- Study completion
- Oct 2025 (estimated)
- First posted
- 5 Feb 2024 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The ORBIT trial is part of a worldwide search for a functional cure of HIV. One such cure strategy aims to reverse HIV in the reservoir from latency by increasing cell-associated HIV-RNA, which will lead to increased antigen presentation, trigger immune recognition, and facilitate the elimination of reservoir cells (so-called 'shock and kill' approach to HIV cure). Participants of the trial are adults with HIV with undetectable viral load that are able to give informed consent to participate in the trial, in total 49 patients will be recruited. The investigational medical compounds in this trial are panobinostat, lenalidomide and pyrimethamine. These are all licensed drugs for other conditions. Participants of this trial will receive a single dose of the IMPs, either as monotherapy or as combination therapy. Sampling will be performed before, during and after medical treatment to evaluate latency reversal, reservoir reduction and safety endpoints. Patients will be recruited from the Erasmus MC, Amsterdam university Medical Center and the University Medical Center Utrecht.
Detailed description
Rationale
Despite advances in antiretroviral therapy (ART) that nowadays can fully suppress HIV replication, HIV treatment still has to be taken lifelong due to the persistence of a latent HIV reservoir. This reservoir consists of long-lived memory T-cells in which HIV persists as provirus in the host genome. There is minimal proviral transcriptional activity, and the elimination of these reservoir cells is prohibited by limited antigen recognition and elimination by the immune system. When antiretroviral treatment is stopped, the virus almost universally rebounds from its reservoir, and if left untreated will result in HIV disease progression. Intensive research efforts over the last decade is focused on finding a definitive cure for HIV that would allow people to safely stop their ART without risking viral rebound. One such cure strategy aims to reverse HIV in the reservoir from latency by increasing cell-associated HIV-RNA, which will lead to increased antigen presentation, trigger immune recognition, and facilitate the elimination of reservoir cells (so-called 'shock and kill' approach to HIV cure). Several latency reversal agents have been identified to reactivate HIV transcription in the reservoir. Though current single latency reversal agents are effective in achieving this to a limited extent, they have not resulted in significant HIV reservoir reduction. One explanation could be that a stronger reactivation is needed. As such, we aim to study novel combinations of promising latency-reversing agents with different drug targets to improve HIV latency reversal within the viral reservoir.
Study design:
Open label randomized controlled trial.
Study population:
49 adult people with HIV-1
Intervention:
The investigational drugs are panobinostat, lenalidomide, and pyrimethamine. Patients will be randomized 1:1:1:1:1:1:1 to one of 7 arms to receive a combination of two investigational drugs, one investigational drug or no interventional treatment.
Arm 1: control Arm 2: panobinostat 20mg once orally Arm 3: lenalidomide 25mg once orally Arm 4: pyrimethamine 200mg once orally Arm 5: panobinostat 20mg once orally and lenalidomide 25mg once orally. Arm 6: panobinostat 20mg once orally and pyrimethamine 200mg once orally. Arm 7: lenalidomide 25mg once orally and pyrimethamine 200mg once orally.
Procedures
All participants will have a screening visit including a leukapheresis or venous blood sampling before the intervention between T= -1 to -60 days. Subsequent blood sampling by phlebotomy is at T=0-hour (day 0) before drug administration, and T=2 hours, T=6 hours, T=24 hours (day 1), and T= 2 months (60 days) post study drug administration. An optional second leukapheresis instead of blood sampling by phlebotomy at the last sampling time point is possible. Clinical assessments are at days 0, 1, and 7. Clinical assessment at day 7 can optionally be remote.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 7
- Model description
- Open label randomized controlled trial.
| Arm | Type | Receives |
|---|---|---|
| control | No intervention | – |
| panobinostat | Experimental | Drug: Panobinostat 20 MG Oral Capsule |
| lenalidomide | Experimental | Drug: Lenalidomide 25 MG Oral Capsule |
| pyrimethamine | Experimental | Drug: Pyrimethamine 200mg Oral Tablet |
| panobinostat + lenalidomide | Experimental | Drug: Panobinostat 20 MG Oral Capsule, Drug: Lenalidomide 25 MG Oral Capsule |
| panobinostat + pyrimethamine | Experimental | Drug: Panobinostat 20 MG Oral Capsule, Drug: Pyrimethamine 200mg Oral Tablet |
| lenalidomide + pyrimethamine | Experimental | Drug: Pyrimethamine 200mg Oral Tablet, Drug: Lenalidomide 25 MG Oral Capsule |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (11 listed)
- Documented HIV-1 infection by 4th generation ELISA, Western Blot or PCR.
- ≥ 18 years old.
- World Health Organization (WHO) performance status 0 or 1.
- Current plasma HIV RNA <50 copies/ml measured on the last 2 occasions, with measurements being at least 3 months apart.
- Uninterrupted prescribed ART for a minimum of two consecutive years.
Key exclusion criteria (14 listed)
- A potential subject who meets any of the following criteria will be excluded from participation in this study:
- Previous exposure to any of the studied LRAs in the last year
- Acute or chronic co-infection with hepatitis B and/or C by the presence of hepatitis B surface antigen (HBsAg) or hepatitis C virus RNA in blood.
- Co-medication with clinically significant interactions with LRA (see chapter 15.h for list)
- Comorbidities affected by LRA compounds, such as but not limited to: known Glucose-6-phospate-dehydrogenase (G6PD) deficiency with anaemia, untreated haemolysis of any cause or hereditary thrombophilia not currently treated by anticoagulation.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Panobinostat 20 MG Oral CapsulePanobinostat 20mg will be administered once orally | Drug | panobinostat, panobinostat + lenalidomide, panobinostat + pyrimethamine |
| Pyrimethamine 200mg Oral TabletPyrimethamine 200mg will be administered once orally | Drug | lenalidomide + pyrimethamine, panobinostat + pyrimethamine, pyrimethamine |
| Lenalidomide 25 MG Oral CapsuleLenalidomide 25mg will be administered once orally | Drug | lenalidomide, lenalidomide + pyrimethamine, panobinostat + lenalidomide |
Primary outcome
Cell-associated HIV RNA
Time frame: 1 day
Fold change in cell-associated HIV RNA
Adverse events
Time frame: 14 days
The number and severity of clinical and biochemical adverse events considered by the investigator to be related to any of the investigational drugs
1 secondary outcome
HIV reservoir
Time frame: 120 days
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 5 Feb 2024.
- Individual participant dataSharing planned: Yes. Data will be stored under FAIR use principle for use in future research. Should external researchers want to use this dataset, they can contact the principal investigator. In the case of adequate privacy standards data can be shared under a specific new Data Sharing Agreement
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
3 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Panobinostat 20 MG Oral Capsule, Pyrimethamine 200mg Oral Tablet and Lenalidomide 25 MG Oral Capsule in people with Hiv, run by Erasmus Medical Center at 3 sites in Netherlands.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 11 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 5 Feb 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 3 sites in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Casper Rokx, MD PhD (+31618069137, c.rokx@erasmusmc.nl), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Cell-associated HIV RNA (time frame: 1 day). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 Feb 2024.